Combination drug therapy for malaria, especially artemisinin-based combination therapy (ACT), is intended to deter resistance by rapidly eliminating malaria parasites using drugs with different mechanisms. The present generation of ACTs was developed without consideration of matching the pharmacokinetic (PK) and pharmacodynamic (PD) properties of partner drugs. Where malaria transmission is high and repeated exposure to new infections is common (namely, in sub-Saharan Africa where ACTs are now being widely deployed), deterring resistance effectively may require matching the PK/PD characteristics of partner drugs to block resistance not only during initial parasite clearance but also during the post-treatment period when new infecting parasites may be exposed to sub-therapeutic levels of unprotected longer-acting partner drugs. This clinical trial follows our observation that chloroquine-sensitive falciparum malaria has reemerged and now predominates following cessation of chloroquine use in Malawi in 1993.In 2005 chloroquine had 99% efficacy against uncomplicated falciparum malaria at our study site in Blantyre, Malawi. As a highly efficacious drug with a long duration of action, known molecular markers for resistance, and a significant likelihood of molecular resistance reemerging under drug pressure, chloroquine in Malawi serves as a unique model for identifying principles to guide the development of combination therapy that will deter the emergence and spread of drug resistance in high transmission settings. With support from this U01 cooperative agreement, we have designed and initiated a randomized, open label, longitudinal clinical trial comparing the efficacy over time of chloroquine alone compared to chloroquine combined with drugs with increasingly longer durations of action (artesunate, azithromycin, or atovaquone proguanil). This study will enable us to define the "window of selection" during which chloroquine (and similar drugs) need to be protected by combination with an effective partner drug to deter the emergence of resistance, and is expected to lead to rational strategies for combining antimalarial drugs to deter the emergence and spread of drug resistant malaria in Africa. Due to administrative delays not under the control of the investigators, the trial started late in year 3 of the cooperative agreement following a successful pilot study. The trial is running smoothly and enrollment is proceeding at or above the projected rate, such that the trial will be completed in less time than originally proposed. No further delays are anticipated and this extension will permit completion of this ongoing unique and important clinical trial.